_______________ WARNINGS AND PRECAUTIONS _______________
`• AMPYRA can cause seizures; the risk of seizures increases with
`increasing AMPYRA doses; discontinue AMPYRA and do not restart if
`a seizure occurs (5.1)
`• AMPYRA should not be taken with other forms of 4-aminopyridine (4-
`AP, fampridine), since the active ingredient is the same (5.3)
`• AMPYRA can cause anaphylaxis. Discontinue and do not restart
`AMPYRA if this occurs (5.4)
` ___________________ ADVERSE REACTIONS ___________________
`The most common adverse events (incidence ≥2% and at a rate greater than
`the placebo rate) for AMPYRA were urinary tract infection, insomnia,
`dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple
`sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and
`pharyngolaryngeal pain (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Acorda
`Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
` ___________________ DRUG INTERACTIONS____________________
`None identified (7)
` ______________ USE IN SPECIFIC POPULATIONS _______________
`•
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`• Nursing Mothers: Discontinue drug or nursing taking into consideration
`importance of drug to mother (8.3)
`• Geriatric use: Because elderly patients are more likely to have decreased
`renal function, it is particularly important to know the estimated CrCl in
`these patients before initiating AMPYRA treatment (4, 5.2, 8.6)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 12/2014
`
`8.5 Geriatric use
`8.6
`Impaired Renal Function
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Special Populations
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, mutagenesis, impairment of fertility
`14 CLINICAL STUDIES
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`17.1 Risk of Seizures
`17.2 AMPYRA dosing
`17.3 Anaphylaxis
`17.4 Storage
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AMPYRA safely and effectively. See full prescribing information for
`AMPYRA.
`
`AMPYRA® (dalfampridine) Extended Release Tablets, for oral use
`Initial U.S. Approval: 2010
` __________________ INDICATIONS AND USAGE _________________
`AMPYRA® (dalfampridine) is a potassium channel blocker indicated to
`improve walking in patients with multiple sclerosis (MS). This was
`demonstrated by an increase in walking speed (1, 14).
` _______________ DOSAGE AND ADMINISTRATION ______________
`• The maximum recommended dose is 10 mg twice daily (approximately
`12 hours apart), with or without food. Tablets should only be taken
`whole; do not divide, crush, chew, or dissolve (2)
`• Estimated creatinine clearance (CrCl) should be known before initiating
`treatment with AMPYRA. In patients with mild renal impairment (CrCl
`51–80 mL/min), AMPYRA may reach plasma levels associated with a
`greater risk of seizures, and the potential benefits of AMPYRA should
`be carefully considered against the risk of seizures in these patients (2,
`5.2, 8.6)
`Patients should not take double or extra doses if a dose is missed. No
`additional benefit was demonstrated at doses greater than 10 mg twice
`daily and adverse events, including seizures, were more frequent at
`higher doses (2)
` ______________ DOSAGE FORMS AND STRENGTHS _____________
`10 mg tablets (3)
` ___________________ CONTRAINDICATIONS ___________________
`• History of seizure (4)
`• Moderate or severe renal impairment (CrCl≤50 mL/min) (4)
`• History of hypersensitivity to AMPYRA or 4-aminopyridine (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Seizures
`5.2 Renal Impairment
`5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine
`5.4 Anaphylaxis
`5.5 Urinary Tract Infections
`ADVERSE REACTIONS
`6.1 Controlled Clinical Trials Experience
`6.2 Other Adverse Reactions
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and delivery
`8.3 Nursing mothers
`8.4
`Pediatric use
`
`6
`
`7
`8
`
`
`
`•
`
` 1
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 1
`
`

`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`AMPYRA (dalfampridine) is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an
`increase in walking speed [see Clinical Studies (14)].
`
` 2
`
`DOSAGE AND ADMINISTRATION
`
`The maximum recommended dose of AMPYRA is one 10 mg tablet twice daily, taken with or without food, and should not be exceeded. Doses
`should be taken approximately 12 hours apart. Tablets should only be taken whole; do not divide, crush, chew, or dissolve. Patients should
`not take double or extra doses if a dose is missed.
`
`Estimated creatinine clearance (CrCl) should be known before initiating treatment with AMPYRA, and monitored at least annually during
`treatment with AMPYRA. CrCl can be estimated using the following equation (multiply by 0.85 for women):
`weight
`age
`kg
`140(
`)
`)
`(
`×
`−
`
`CrCl
`=
`SerumCr
`mg
`dl
`72
`)
`/
`(
`×
`
`
`In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a
`dose that may be associated with an increased risk of seizures. As mild renal impairment is common after age 50, estimating CrCl is particularly
`important in these patients. The potential benefits of AMPYRA should be carefully considered against the risk of seizures in these patients [see
`Warnings and Precautions (5.2) and Clinical Pharmacology (12.4)].
`
`No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations because of adverse
`reactions were more frequent at higher doses [see FDA-Approved Patient Information for complete “Instructions for Use”].
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`AMPYRA is available in a 10 mg strength and is a film-coated, white to off-white, biconvex, oval shaped, non-scored tablet with flat edge,
`debossed with “A10” on one side.
`
` 4
`
`CONTRAINDICATIONS
`
`The use of AMPYRA is contraindicated in the following conditions:
`History of seizure
`•
`• Moderate or severe renal impairment (CrCl≤50 mL/min)
`History of hypersensitivity to AMPYRA or 4-aminopyridine
`•
`
` 5
`
`WARNINGS AND PRECAUTIONS
`
`Seizures
`5.1
`AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9–14 weeks
`duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with
`dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY).
`In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a
`history of seizures, and generally within days to weeks of starting therapy.
`
`AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients
`were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially
`higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure
`while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4)].
`
`Renal Impairment
`5.2
`AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4)].
`
`Because patients with moderate to severe renal impairment (CrCl ≤50mL/min) would require a dose lower than 10 mg twice daily and no strength
`smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4)].
`
`In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a
`dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1)].
`
`Concurrent Treatment with Other Forms of 4-Aminopyridine
`5.3
`AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should
`discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-
`related adverse reactions.
`
`Anaphylaxis
`5.4
`AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and
`angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue
`AMPYRA and seek immediate medical care should these signs and symptoms occur (17.3).
`
`Urinary Tract Infections
`5.5
`Urinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg
`twice daily (12%) as compared to placebo (8%). UTIs in AMPYRA-treated patients should be evaluated and treated as clinically indicated.
`
`
`
`
`
`
`2
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 2
`
`

`
`ADVERSE REACTIONS
`6
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be
`directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
`
`The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and
`Urinary Tract Infections.
`
`Controlled Clinical Trials Experience
`6.1
`In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily
`experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The
`treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more
`frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness
`(AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).
`
`Table 1 lists adverse reactions that occurred in ≥2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-
`treated patients, in controlled clinical trials.
`
`Table 1: Adverse reactions with an incidence ≥2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to
`placebo in controlled clinical trials
`
`
`Adverse Reaction
`
`Placebo
`(N=238)
`
`Urinary tract infection
`Insomnia
`Dizziness
`Headache
`Nausea
`Asthenia
`Back pain
`Balance disorder
`Multiple sclerosis relapse
`Paresthesia
`Nasopharyngitis
`Constipation
`Dyspepsia
`Pharyngolaryngeal pain
`
`8%
`4%
`4%
`4%
`3%
`4%
`2%
`1%
`3%
`3%
`2%
`2%
`1%
`1%
`
`AMPYRA
`10 mg twice daily
`(N=400)
`12%
`9%
`7%
`7%
`7%
`7%
`5%
`5%
`4%
`4%
`4%
`3%
`2%
`2%
`
`
`Other Adverse Reactions
`6.2
`AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA
`for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety
`profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has
`been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-
`years (95% confidence interval 0.13–0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21–6.28).
`
` 7
`
`DRUG INTERACTIONS
`
`In humans, dalfampridine is eliminated predominantly unchanged by the kidneys. No clinically significant drug interaction was identified. In
`particular, no interaction was identified between dalfampridine and baclofen [see Clinical Pharmacology, Pharmacokinetics (12.3)].
`
` 8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C
`There are no adequate and well-controlled studies of AMPYRA in pregnant women. Administration of dalfampridine to animals during
`pregnancy and lactation resulted in decreased offspring viability and growth at doses similar to the maximum recommended human dose
`(MRHD) of 20 mg/day. AMPYRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`In developmental toxicity studies in rats and rabbits, dalfampridine was administered orally at doses up to 10 and 5 mg/kg/day, respectively,
`during the period of organogenesis. These doses are approximately 5 times the MRHD on a body surface area (mg/m2) basis. No evidence of
`developmental toxicity was found in either species at the highest doses tested, which were maternally toxic. Oral administration of dalfampridine
`(at doses of 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to rats throughout the pregnancy and lactation
`periods resulted in decreased offspring survival and growth. The no-effect dose for pre- and postnatal developmental toxicity in rats (1 mg/kg) is
`approximately 0.5 times the MRHD on a mg/m2 basis.
`
`Labor and delivery
`8.2
`The effect of AMPYRA on labor and delivery in humans is unknown.
`
`
`
`
`
`
`
`3
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 3
`
`

`
`Nursing mothers
`8.3
`It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential
`for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue
`the drug, taking into account the importance of the drug to the mother.
`
`Pediatric use
`8.4
`Safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established.
`
`Geriatric use
`8.5
`Clinical studies of AMPYRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than
`younger subjects. A population PK analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to
`necessitate a modification of dose with age. Other reported clinical experience has identified no differences in responses between the elderly and
`younger patients.
`
`AMPYRA is known to be substantially excreted by the kidneys and the risk of adverse reactions, including seizures, is greater with increasing
`exposure of dalfampridine. Because elderly patients are more likely to have decreased renal function, it is particularly important to know the
`estimated creatinine clearance (CrCl) in these patients [see Warnings and Precautions (5.2)].
`
`Impaired Renal Function
`8.6
`Clearance of dalfampridine is decreased in patients with renal impairment and is significantly correlated with creatinine clearance (CrCl) [see
`Clinical Pharmacology, Special Populations (12.4)]. AMPYRA is contraindicated in patients with moderate or severe renal impairment (CrCl
`≤50 mL/min) [see Contraindications (4)]. The risk of seizures in patients with mild renal impairment (CrCl 51–80 mL/min) is unknown, but
`dalfampridine plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an
`increased risk of seizures. If unknown, estimated creatinine clearance should be calculated prior to initiating treatment with AMPYRA [see
`Dosage and Administration (2) and Warnings and Precautions (5.2)].
`
`OVERDOSAGE
`10
`Three cases of overdose were reported in controlled clinical trials with AMPYRA, involving two MS patients. The first patient took six times the
`currently recommended dose (60 mg) and was taken to the emergency room with altered mental state. The second patient took 40 mg doses on
`two separate occasions. In the first instance, she experienced a complex partial seizure and, in the second instance, a period of confusion. Both
`patients recovered by the following day without sequelae.
`
`Several cases of overdose are found in the scientific literature in which various formulations of dalfampridine were used, resulting in numerous
`adverse events including seizure, confusion, tremulousness, diaphoresis, and amnesia. In some instances, patients developed status epilepticus,
`requiring intensive supportive care and were responsive to standard therapy for seizures. In one published case report, an MS patient who
`ingested 300 mg of 4-aminopyridine (dalfampridine) developed a condition that resembled limbic encephalitis. This patient developed weakness,
`reduced awareness, memory loss, hypophonic speech, and temporal lobe hyperintensities on MRI. The patient’s speech and language and
`ambulation improved over time, and an MRI at 4 months after the overdose no longer showed signal abnormalities. At one year, the patient
`continued to have difficulty with short term memory and learning new tasks.
`
`DESCRIPTION
`11
`AMPYRA (dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg dalfampridine,
`formulated as an extended release tablet for twice-daily oral administration. Dalfampridine is also known by its chemical name, 4-aminopyridine,
`with the following structure:
`
`
`AMPYRA (dalfampridine) Extended Release tablets are available in a 10 mg strength and are white to off-white, biconvex, oval shaped, film-
`coated, non-scored tablets with flat edge, debossed with “A10” on one side, containing 10 mg of dalfampridine. Inactive ingredients consist of
`colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium
`dioxide.
`
`Dalfampridine is a fine white powder with a molecular weight of 94.1, CAS 504-24-5, and a molecular formula of C5H6N2. At ambient
`conditions, dalfampridine is soluble in water, methanol, acetone, tetrahydrofuran, isopropanol, acetonitrile, N,N-dimethylformamide,
`dimethylsulfoxide, and ethanol.
`
`CLINICAL PHARMACOLOGY
`12
`Mechanism of action
`12.1
`The mechanism by which dalfampridine exerts its therapeutic effect has not been fully elucidated. Dalfampridine is a broad spectrum potassium
`channel blocker. In animal studies, dalfampridine has been shown to increase conduction of action potentials in demyelinated axons through
`inhibition of potassium channels.
`
`Pharmacodynamics
`12.2
`AMPYRA does not prolong the QTc interval and does not have a clinically important effect on QRS duration.
`
`Pharmacokinetics
`12.3
`Absorption and Distribution:
`Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of extended release
`AMPYRA tablets has not been assessed, but relative bioavailability is 96% when compared to an aqueous oral solution. The extended release
`tablet delays absorption of dalfampridine relative to the solution formulation, giving a slower rise to a lower peak concentration (Cmax), with no
`effect on the extent of absorption (AUC). Single AMPYRA tablet 10 mg doses administered to healthy volunteers in a fasted state gave peak
`
`4
`
`
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 4
`
`

`
`Special Populations
`
`concentrations ranging from 17.3 ng/mL to 21.6 ng/mL occurring 3 to 4 hours post-administration (Tmax). In comparison, Cmax with the same
`10 mg dose of dalfampridine in an oral solution was 42.7 ng/mL and occurred approximately 1.3 hours after dosing. Exposure increased
`proportionally with dose.
`
`Dalfampridine is largely unbound to plasma proteins (97–99%). The apparent volume of distribution is 2.6 L/kg.
`
`There is no apparent difference in pharmacokinetic parameter values following administration of AMPYRA tablets to either healthy volunteers or
`patients with MS.
`
`When dalfampridine is taken with food, there is a slight increase in Cmax (12–17%) and a slight decrease in AUC (4–7%). These changes in
`exposure are not clinically significant, and therefore the drug may be taken with or without food [see Dosage and Administration (2)].
`
`Metabolism and Elimination:
`Dalfampridine and metabolites elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in
`feces. Most of the excreted radioactivity in urine was parent drug (90.3%). Two metabolites were identified: 3-hydroxy-4-aminopyridine (4.3%)
`and 3-hydroxy-4-aminopyridine sulfate (2.6%). These metabolites have been shown to have no pharmacologic activity on potassium channels.
`
`The apparent elimination half-life of dalfampridine following administration of the extended release tablet formulation of AMPYRA is 5.2 to 6.5
`hours. The plasma half-life of the sulfate conjugate is approximately 7.6 hours and the half-life of 3-hydroxy-4-aminopyridine could not be
`calculated because concentrations for most subjects were close to or below the limit of quantitation.
`
`In vitro studies with human liver microsomes indicate that CYP2E1 was the major enzyme responsible for the 3-hydroxylation of dalfampridine.
`The identity of the CYP enzymes suspected of playing a minor role in the 3-hydroxylation of dalfampridine could not be established
`unequivocally.
`
`12.4
`Pediatric
`The safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established.
`
`Geriatric
`A population pharmacokinetic analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to
`necessitate a modification of dose.
`
`Gender
`A population pharmacokinetic analysis suggested that female patients would be expected to have higher maximum dalfampridine plasma
`concentration than male patients. The magnitude of these differences is small and does not necessitate any dose modification.
`
`Renal Impairment [see Contraindications (4) and Warnings and Precautions, Renal Impairment (5.2)].
`The pharmacokinetics of dalfampridine was studied in 9 male and 11 female subjects with varying degrees of renal function. Elimination of the
`drug is significantly correlated with the creatinine clearance. Total body clearance of dalfampridine was reduced by about 45 % in patients with
`mild renal impairment (CrCl 51–80 mL/min), by about 50% in patients with moderate renal impairment (CrCl = 30–50 mL/min), and by about
`75% in patients with severe renal impairment (CrCl <30 mL/min). The terminal half-life of dalfampridine is about 3.3 times longer in patients
`with severe renal impairment but is not prolonged in patients with mild or moderate renal impairment.
`
`Hepatic Impairment
`The pharmacokinetics of dalfampridine in hepatically impaired subjects has not been studied. Since dalfampridine is primarily excreted
`unchanged in the urine, hepatic impairment is not expected to significantly affect dalfampridine pharmacokinetics or recommended dosing.
`
`Race
`There were too few non-Caucasians in the patient population to evaluate the effect of race.
`
`Drug Interactions
`Effects of Co-administered Drugs on Dalfampridine
`Interferon
`Dalfampridine kinetics were not affected by co-administration of subcutaneous injections of 8 million units interferon beta-1b.
`
`Baclofen
`Based on a population analysis, dalfampridine kinetics were not affected by baclofen.
`
`Effects of Dalfampridine on Co-administered Drugs
`In vitro data with human liver microsomes showed that dalfampridine was not a direct or time-dependent inhibitor of CYP1A2, CYP2A6,
`CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Dalfampridine is not likely to affect the pharmacokinetics of drugs that are
`substrates of these enzymes.
`
`Other in vitro studies with cultured human hepatocytes with 0.025 μM, 0.25 μM, 2.5 μM, and 25 μM dalfampridine had little or no effect on
`CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzyme activities. Consequently, the potential for dalfampridine to induce
`human hepatocytes at therapeutic concentrations is remote.
`
`In vitro, dalfampridine is not a substrate or an inhibitor for the p-glycoprotein transporter. The pharmacokinetics of AMPYRA are unlikely to be
`affected by drugs that inhibit the p-glycoprotein transporter, and dalfampridine is not likely to affect the pharmacokinetics of drugs that are
`substrates of the p-glycoprotein transporter.
`
`
`
`
`
`
`5
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 5
`
`

`
`NONCLINICAL TOXICOLOGY
`13
`Carcinogenesis, mutagenesis, impairment of fertility
`13.1
`Carcinogenesis: Two year dietary carcinogenicity studies of dalfampridine were conducted in mice and rats. In mice, the doses tested
`(approximately 2, 12.5, and 80 mg/kg/day) were associated with plasma exposures (AUC) up to 11 times the plasma AUC in humans at the
`maximum recommended human dose (MRHD) of 20 mg/day. There was no evidence of drug-related carcinogenicity.
`
`In rats, the doses tested (approximately 2, 6, and 18 mg/kg/day) were approximately 1, 3, and 9 times the MRHD on a body surface area (mg/m2)
`basis. There was a significant increase in uterine polyps at the highest dose tested.
`
`Mutagenesis: Dalfampridine was negative in in vitro (bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration) and in vivo
`(mouse bone marrow, rat erythrocyte micronucleus) genetic toxicology assays.
`
`Impairment of Fertility: Oral administration of dalfampridine (doses of 1, 3, and 9 mg/kg/day) to male and female rats prior to and throughout
`mating, and continuing in females up to day 13 of gestation or day 21 of lactation resulted in no adverse effects on fertility. Reduced offspring
`viability and body weight were observed at 9 mg/kg/day. The mid dose (a no-effect dose) was similar to the MRHD on a mg/m2 basis.
`
`CLINICAL STUDIES
`14
`The effectiveness of AMPYRA in improving walking in patients with multiple sclerosis was evaluated in two adequate and well controlled trials
`involving 540 patients. Patients in these two clinical trials had a mean disease duration of 13 years and a mean Kurtzke Expanded Disability
`Status Scale (EDSS) score of 6.
`
`Trial 1 was a randomized, placebo-controlled, parallel group, 21-week study (one week post screening, two-week, single-blind placebo run-in,
`14-week double-blind treatment, and 4-week no treatment follow-up) in 301 patients with multiple sclerosis at 33 centers in the U.S. and Canada:
`229 patients assigned to AMPYRA 10 mg twice daily and 72 patients assigned to placebo. A total of 283 patients (212 AMPYRA and 71
`placebo) completed all study visits. Patient inclusion criteria included the ability to walk 25 feet in 8–45 seconds. Patient exclusion criteria
`included a history of seizures or evidence of epileptiform activity on a screening EEG, and onset of an MS exacerbation within 60 days.
`
`Trial 2 was a randomized, placebo-controlled, parallel group, 14-week study (one week post-screening, two weeks of single-blind, placebo run-in,
`nine weeks of double-blind treatment, and two weeks of no-treatment follow-up) in 239 patients with multiple sclerosis at 39 centers in the U.S.
`and Canada: 120 patients assigned to 10 mg twice daily and 119 assigned to placebo. A total of 227 patients (113 AMPYRA and 114 placebo)
`completed all study visits. The patient inclusion and exclusion criteria used in Trial 1 were employed in Trial 2, and in addition patients with
`severe renal impairment were also excluded.
`
`The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a
`responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during
`the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period
`and one after).
`
` A
`
` significantly greater proportion of patients taking AMPYRA 10 mg twice daily were responders, compared to patients taking placebo, as
`measured by the T25FW (Trial 1: 34.8% vs. 8.3%; Trial 2: 42.9% vs. 9.3%). The increased response rate in the AMPYRA group was observed
`across all four major types of MS disease course.
`
`During the double-blind treatment period, a significantly greater proportion of patients taking AMPYRA 10 mg twice daily had increases in
`walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo (Figure 1 and Figure 2).
`
`Figure 1: Average walking speed change (%) from baseline during the double-blind phase of Trial 1
`
`100%
`
`
`
`6
`
`
`
`
`
`p=0.001
`
`Placebo (N=72)
`
`AMPYRA 10 mg b.i.d (N=224)
`
`p=0.001
`
`p<0.001
`
`p=0.005
`
`p=0.258
`
`p>0.99
`
`p>0.999
`
`90%
`
`80%
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Patients (%)
`
`≥ 0%
`
`≥ 50%
`≥ 40%
`≥ 30%
`≥ 20%
`≥ 10%
`Average Percent Increase in Walking Speed from Baseline
`
`≥ 60%
`
`P values provided at each threshold comparing AMPYRA to placebo.
`
`
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1139 PAGE 6
`
`

`
`
`
`Figure 2: Average walking speed change (%) from baseline during the double-blind phase of Trial 2
`
`p=0.008
`
`p=0.002
`
`Placebo (N=118)
`
`AMPYRA 10 mg b.i.d (N=119)
`
`p<0.001
`
`p<0.001
`
`p=0.333
`
`p>0.99
`
`≥ 0%
`
`≥ 50%
`≥ 40%
`≥ 30%
`≥ 20%
`≥ 10%
`Average Percent Increase in Walking Speed from Baseline
`
`p>0.999
`
`≥ 60%
`
`100%
`
`90%
`
`80%
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Patients (%)
`
`P values provided at each threshold comparing AMPYRA to placebo.
`
`
`In Trial 1 and Trial 2, consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of
`ambulatory disability, the 12-item Multiple Sclerosis Walking Scale (MSWS-12), for both drug and placebo treated patients. However, a drug-
`placebo difference was not established for that outcome measure.
`
`The majority of patients in these trials (63%) were using immunomodulatory drugs (interferons, glatiramer acetate, or natalizumab), but the
`magnitude of improvement in walking ability was independent of concomitant treatment with these drugs. No differences in effectiveness based
`on degree of impairment, age, gender, or body mass index were detected. There were too few non-Caucasians in the patient population to
`evaluate the effect of race.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`AMPYRA (dalfampridine) extended release tablets, 10 mg are film-coated, white to off-white, biconvex, oval shaped, non-scored tablets with flat
`edge. The tablets are identified by a debossed code “A10” on one side and are available in bottles of 60.
`NDC 10144-427-60 bottles of 60 tablets
`•
`Store at 25°C (77°F). Excursions permitted 15–30ºC (59–86ºF).
`
`PATIENT COUNSELING INFORMATION
`17
`See FDA-approved Patient Labeling
`
`Risk of Seizures
`17.1
`Inform patients that AMPYRA can cause seizures, and that they must discontinue use of AMPYRA if they experience a seizure.
`
`AMPYRA dosing
`17.2
`Instruct patients to take AMPYRA exactly as prescribed. Instruct patients not to take a double dose after they miss a dose, as this would increase
`their risk of seizure. Instruct patients not to take more than 2 tablets in a 24-hour period and to make sure that there is an approximate 12-hour
`interval between doses.
`
`Anaphylaxis
`17.3
`Advise patients to discontinue AMPYRA and seek medical care if they develop signs and symptoms of anaphylaxis.
`
`Storage
`17.4
`Advise patients to store AMPYRA at 25°C (77°F), with excursions permitted to 15–30ºC (59–86ºF). Advise patients to safely throw away
`AMPYRA that is out of date or no longer needed.
`
`
`
`MEDICATION GUIDE
`AMPYRA® (am-PEER-ah)
`(dalfampridine)
`Extended Release Tablets
`
`
`Read this Medication Guide before you start taking AMPYRA and each time you get a refill. There may be new information. This information
`does not take the place of talking with your doctor about your medical condition or your treatment.
`
`What is the most important information I should know about AMPYRA?
`AMPYRA can cause seizures.
`You could have a seizure even if you never had a seizure before.
`•
`Your chance of having a seizure is higher if you take too much AMPYRA or if your kidneys have a mild decrease of function, which
`•
`is common after age 50.
`Your doctor may do a bloo